The Pima Indians have the highest reported prevalence and incidence rate of non-insulin dependent diabetes mellitus (NIDDM) of any population in the world. In this study we are longitudinally examining Pima Indians to determine the sequence of metabolic events that occur with the development of NIDDM to isolate the metabolic predictor of this debilitating disease. Studies are done on our clinical research ward on obese, adult, Pima Indians, who are at the highest risk of the development of NIDDM. They are admitted to the clinical research ward for 7-10 days to characterize their insulin and carbohydrate metabolism both in vivo and in vitro. The results to date have shown that the Pima Indians are hyperinsulinemic compared to Caucasians, as well as more insulin resistant. The insulin resistance cannot be attributed solely to degree of obesity. A substantial portion of the variability in insulin resistance is familial in nature, and therefore likely to be genetically determined. The development of impaired glucose tolerance is associated with a worsening of insulin resistance and not any deficit in insulin secretion. Insulin resistance also appears to be a predictor of the development of the disease among the 18 subjects who have developed diabetes out of the initial 165 who entered the study. The insulin resistance was predictive of the disease independent of the effect of obesity.